Plasma Cell Diseases (…and some Bonus

Content!) SethPolitanoDOFACPAssociateProgramDirector

ClinicalAssistantProfessorofMedicineKeckSchoolofMedicineofUSC

Plasma Cell Dyscrasias • Clonalplasmaorlymphoplasmacyticdiseases• DetectablemonoclonalAb(M-Protein)intheserumorurine• Canbeheavychain(IgG,IgA,IgD,IgM)withaκorλlightchainORκorλdiseasealonewithoutaheavychainorheavychainalone

α1α2β1β2γ

Alpha1Region:A1AntitrypsinAFP

HDLVLDLAlpha2Region:Haptoglobin CeruloplasminAntithrombin3BetaRegion:TransferrinHemoglobinCRPC3BetalipoproteinGammaRegion:Immunoglobulins

Intro to Protein Electrophoresis

Plasma Cell Dyscrasias – The Tests • SPEPanUPEP:CantellifthereisanM-protein,andhowmuch,butnottheactualchainsubtype

• Freelightchainanalysistellsusamountofthesecomponentsnotcomplexedtoheavychains-reportedasratioofκ/λ(normalisapprox.3-1.7)

•  Immunofixationtestingtellsustheactualchainsubtypes

Plasma Cell Dyscrasias – The Tests

•  Inadditiontovariousfindingsonlabsandimaging(morelater)–thinkofthisspectrumofdiseaseswith:

•  “M-spike”onelectrophoresismapping(above)•  ElevatedTotalGammaGlobulinConcentrationonlabs•  QuantitativeImmunoglobulinLevelswithoneelevated(ieIgG)andtherest

suppressed•  κ/λofusually>2(muchhigherinactualcases)

Multiple Myeloma • Malignantclonaldisorderofplasmacells•  2ndmostcommonhematologicmalignancy• Peakincidencein60s• Riskfactorsincluderace(AfricanAmerican),andmodestincreasewithradiation/chemicalexposure

Multiple Myeloma – Clinical Presentation/clues •  20%areasymptomatic•  Fatigueanddyspnea•  Hypercalcemia•  RenalFailure•  BonePain•  PathologicFractures•  NeurologicComplications•  RecurrentInfections•  BleedingTendency•  Cryoglobulinema•  AMS/BlurredVision/Headache/HeartFailure/Dyspnea•  Canprogresstoamyloidosis

Multiple Myeloma – Clinical Presentation/clues Workupevaluation–tellmeaboutthe:

CBC

BloodSmear

Ua

BMP

LiverPanel

Multiple Myeloma – Clinical Presentation/clues Whatotherworkupshouldbedone?

• SPEPandIF• UPEPandIF• Serumlightfreechainanalysistogetkappa/lambda

• QuantitativeImmunoglobulinLevels

Multiple Myeloma – Clinical Presentation/clues

MonoclonalSpike/LightchainsinUrine

RaisedIgGorIgA(IgM,IgD,andIgEmyelomascanbeseenbutrarely).

Multiple Myeloma

Bone Survey (not a Bone Scan). If negative – MRI or PET

Check Spine, Skill, Pelvis, Humeri and Femurs

Multiple Myeloma

Multiple Myeloma DiagnosticCriteria:ThediagnosisofSymptomaticmultiplemyelomarequires???

1) MProteinPresent(aka“TheSpike”)–THEAMOUNTDOESNOTMATTERFORDX)2)  PlasmaCells>10%orPlasmocytoma3)  SignofOrganDysfunction(atleast1)

§  Ca>11.5§  Cr>2§  Hgb<10§  LyticLesions§  Amyloidosis§  Hyperviscosity§  BacterialInfections(>2inprevious12months)

What if a hospitalized patient with pneumonia has a globulin gap on admit labs? There is normal Cr, no symptoms of lytic disease, normal calcium and normal hemoglobin. You send an SPEP which reveals a 2.8 g/dL monoclonal spike…

MGUS: •  No Evidence of Symptomatic Disease •  <10% Plasma Cells •  There is an M-Spike of IgG or IgA, but it is Less than 3 g/dL

•  MGUS is seen in 1% of individuals at age 50, 7% in those older than 85

•  Osteoporosis is common in MGUS

•  1-2% Annual Transformation into Multiple Myeloma, overall risk 20%

• ThepresenceofanIgAorIgMgammopathy,anMproteinlevelof1.5g/dLormore,andanabnormalserumFLCratioarepredictiveofprogressiontomultiplemyelomaorotherPCDinnon–light-chainMGUS

• Oninitialeval,quantifyMproteinlevelandFLClevel•  Ifnoriskfactorsforprogression:Canfollow-upwithyearlyhistoryandphysicalexam.Considerlabevaluationq2-3years

•  Ifatleastoneriskfactor:Yearlyhistory,examandlabs•  FollowupconsistsofCBC,Calcium,CrandMproteinLevels.Others(ieimaging)guidedbyexam/symptoms

•  IfpatienthasincreasedMprotein,clinicallyevidentdisease(symptoms/exam/labs),orabnormalFLCratio,furtherw/upforMMisneededwithaBMbiopsy.

•  ConsiderbaselineDEXAinallpatientswithMGUS

MGUS Follow up/Approach

SmolderingMM:•  NoEvidenceofSymptomaticDisease•  ≥10%PlasmaCells•  ThereisanM-SpikeofIgGorIgA,butitisAtLeast3g/dL•  Thesepatientshaveahigherrateofconversationtomultiple

myeloma,soveryclosefollow-upisneeded•  Oninitialevaluation,MRIisusuallydonetoassessforbonelesions•  Indicationstotreat:

•  Bonelesions•  AbnormalFLCRatio•  PlasmaCells>60%onBiopsy

Stagingandrisk:

Ifpresent,theseshouldbeaddressedimmediately•  SevereAnemia

•  RenalFailure

•  Hypercalcemia

•  LyticLesions

•  CompressionFractures

•  Hyperviscosity

Treatment

Treatment Whydoweneedtoaddressallofthesementioned?

• AllPatients<70withGoodPerformanceStatusshouldbeconsideredforPBSCT

•  Initialinductionregimendependsonifpatientisacandidateforhigh-dosechemotherapywithautologousperipheralbloodstemcelltransplantation(PBSCT).

•  ZoledronicAcidimprovespainandsurvival

•  InductionConsistsofanycombinationofThalidomide/LenalidomideBortezomibSteroidsMelphalanCyclophosphamide

•  PBSCTtypicallyundergoinitialtherapywithregimensthatavoidalkylatingagentsbecausethesedrugsdamagestemcellsandimpairtheircollectioninadequatenumbers.

•  Afterinductiontherapy,multipleregimens,usuallyincludinglenalidomide,areusedformaintenancetherapy

Treatment

Mostpatientswillrelapse,evenwithPBSCT• Ifpriorlong-responseduration,repeatedinductiontherapyused• Ifnot,usuallyissingleorcombochemowithnewagent• Relapsedpatientsreceivedifferentclassesofmedication,includecarfilzomib,andotherimmunomodulatoryagents(suchaspomalidomide)

Treatment

Quiz SideeffectofThalidomide?Thrombosis(especiallyifgettingsteroidsandpatientsimmobilized)PeripheralNeuropathyFatigueConstipationWhatelseisitusedfor?ErythemaNodosumLeprosumSideeffectofBortezomib?ThrombocytopeniaPeripheralNeuropathy

Prevention of Infections • AnnualInfluenza• Pneumococcalvaccination• IVIGisgiventosomepatientswithlowIGlevelsandrecurrentinfections

• IndolentB-cellnon-Hodgkinlymphoma• IgMκorλMprotein• Classifiedsimilartomyeloma(i.esmolering/symptomatic)

Waldenström Macroglobulinemia

• Commonlypatientshavefatigueandanemia• Beingalymphoma,“Bsymptoms”arealsoprominent• Bleedingcanbeseenuponpresentation(hyperviscosity,plateletdysfunctionetc)• Hyperviscosity–headache,hearingloss,tinittus,blurryvision,AMS• Abdominalpainfromliver/spleeninfiltration• Neuropathy• Canpresentwithcryoglobulinemiaandcoldagglutinindisease.

Waldenström Macroglobulinemia

UNLIKEMULTIPLEMYELOMA:1)  Amyloidisrare2)  Lyticlesionsarerare3)  Renalinsufficiencyisrare

Waldenström Macroglobulinemia

Physicalexamwiththesepatients:• Lymphadenopathyandhepatosplenomegalyarecommon• Funduscopicexammayrevealdilatedretinalveins,papilledema,andflamehemorrhages

Waldenström Macroglobulinemia

• Workupissimilartomyeloma(SPEPandIFwithmonoclonalGammaGlobulinoftheIgMclass)

• Evaluateforbleedingdisorderswithcoagulationpanel

• Watchforhemolysis/skinfindingsofcryoandworkupasneeded

• PrognosisdeterminedbyLDH,β2-microglobulinandalbumin

• DiagnosismadeviaBoneMarrowBiopsy

Waldenström Macroglobulinemia

• Ifthereisaconcernforhyperviscosity,treatmentincludesplasmapheresis

• AutologousHSCThasbeenusedinsomepatients

• Otherwise,treatmentisrituximab+alkylatingagent(chlorambucil,cyclophosphamide,bendamustine)orapurineanalog(fludarabine,cladribine)orbortezomibwithorwithoutaglucocorticoid.Ibrutinibrecentlyapproved

Waldenström Macroglobulinemia

A52-year-oldmanisevaluatedforlowbackpainof3months'durationthatisnonradiating,progressive,andworsewithambulation.Hereportsnoprecedinginjury.Medicalhistoryisnotableforsmolderingmultiplemyelomadiagnosed1yearago;hehasbeenstablesincethattime.Hisonlymedicationisas-neededacetaminophen.Onphysicalexamination,temperatureis36.8,bloodpressureis132/82,pulserateis70,andrespirationrateis14.Nofocalneurologicfindingsarenoted.Hehaspaintopalpationofthelowerlumbarspine.Theremainderoftheexaminationisunremarkable.Laboratorystudiesshowahemoglobinlevelof13,serumcreatininelevelof1.0andserumcalciumlevelof9.8.Plainradiographsofthelumbosacralspinedemonstratenolyticlesionsorfractures.

Whatisthemostappropriatenextstep?1)  Observationwithcontinuedlabevaluation2)  ZoledronicAcid3)  MRIoftheLumbarSpine4)  ReferralforChemotherapy5)  Lidocainepatchwithhydrocodoneforbreakthroughpain

A56-year-oldwomanisevaluatedforanelevatedserumproteinleveldiscoveredduringaroutineexaminationforalifeinsurancepolicy.Sheisasymptomatic.Medicalandfamilyhistoriesareunremarkable,andshetakesnomedications.Onphysicalexamination,vitalsignsarenormal,andtheremainderoftheexaminationisunremarkable.

Hgb 13.4

LeukocyteCount 6400

Platelets 224,000

Calcium 9.6

Cr 0.7

Albumin 3.9

IgG 2080(Elevated)

SerumproteinelectrophoresisandimmunofixationrevealamonoclonalIgGbandmeasuring0.8g/dL.A24-hoururineproteinelectrophoresisreveals80mgoftotalproteinandtracemonoclonalfreeκlightchainsthataretoolowtoquantify.Abonemarrowaspirateandbiopsyrevealsclonalplasmacellsrepresenting8%oftheoverallmarrowcellularity.Askeletalsurveydemonstratesnolyticlesions,osteopenia,orfractures.Whatisthemostappropriatenexttest?1)  MRIofthecervical,thoracicandlumbarspine2)  SerumFreeLightChainTesting3)  SerumLDH4)  RepeatBoneMarrowBiopsy5)  SerumB2-microglobumin

A72-year-oldmanisevaluatedfora6-monthhistoryofprogressivefatigue,dyspneawithexertion,intermittentdrenchingnightsweats,anda6.8-kg(15-lb)weightloss.Medicalhistoryisunremarkable,andhetakesnomedications.Onphysicalexamination,thepatientappearsfatigued.Temperatureis37.0°C(98.6°F),bloodpressureis148/86mmHg,pulserateis88/min,andrespirationrateis16/min.BMIis24.Neurologicandfunduscopicexaminationsarenormal.Lungsarecleartoauscultation.Rubbery,1.5-to2.5-cmlymphnodesarepalpableinthebilateralanteriorcervicallymphnodechains,rightaxilla,andbilateralinguinalregions.Thespleenispalpable2cmbelowthemidleftcostalmargin.

Hgb 9.4

Leukocytes 5400

Platelets 184000

ReticCount 1.5%

BUN 20

Cr 1.1

IgG,IgA,IGM 540,80,3880

LDH 120

TotalProtein 9.3

BloodsmearisunremarkablewiththeexceptionofreducedRBCs.Coombsisnegative.SPEP/IFrevealsmonoclonalIgMbandof3.2g/dL.BMBiopsyrevealsclonalplasmacells,plasmacytoidlymphocytes,andmatureBcells,representing50%oftheoverallmarrowcellularitywithouterythroidhyperplasia.CToftheneck,chest,abdomen,andpelvisdemonstratessplenomegalyandcervical,axillary,mesenteric,andinguinallymphadenopathywithlymphnodesmeasuringupto3cm.Thelungfieldsareclear.

Whichofthefollowingisthemostappropriatemanagement?1)  ColdAgglutinTitier2)  PlasmaExchange3)  RituximabplusChemotherapy4)  JAK2Testing5)  ThalidomideplusDexamethasone

Bonus Topics… YAY!

A68-year-oldmanisevaluatedfora6-monthhistoryofprogressivedyspneaonexertion,dizzinessonstanding,lowerextremityedema,andburningpainwithnumbnessinhisextremities.Healsonotesintermittentloosestoolsupto6timesdaily.Medicalhistoryisotherwiseunremarkable,andhetakesnomedications.Heiscurrentwithscheduledhealthmaintenancescreeninginterventions,andlaboratorystudiesobtained3yearsagoforaninsurancephysicalexaminationwerenormal.Onphysicalexamination,temperatureisnormal,pulserateis90,andrespirationrateis20.Bloodpressureis140/70mmHgsitting;uponstanding,bloodpressuredropsto90/60mmHgwithdizziness.BMIis27.Estimatedcentralvenouspressureis7cmH2O.Decreasedbreathsoundsareheardatthelungbasesbilaterally.Heartexaminationdoesnotrevealaruborgallop.Abdominalexaminationrevealsmildhepatosplenomegaly.Onneurologicexamination,thereisimpairedtouchandvibrationsenseinagloveandstockingdistribution.Bilaterallowerextremityedemaisnotedtotheleveloftheankles.

EKGrevealsLowvoltageinthelimbleads.Echocardiogramrevealsamildpericardialeffusion,restrictivefillingpatternwithandEFof65%,andincreasedechogenicityofthemyocardiumDiagnosis?Thoughts?

Albumin 2.8

Electrolytes Normal

FastingPlasmaGlucose 90

Ua 3+protein,noblood/casts

UrineP/Cr 4.8

• ExtracellulardepositionofLMWProteins• Manyformsoccurincluding:

• Otherformsincludehereditary,senile,dialysisandorgan-specificrelatedamyloid

Amyloidosis

Type Diseases Amyloid

ALAmyloidosis Plasmacelldyscrasia Monoclonalfreeλorκlightchains

AAamyloidosis

Rheumatoidarthritis,inflammatoryboweldisease,familialMediterraneanfever,chronicinfection

SerumamyloidAprotein

Amyloid - Clinical Ofnote,apatientmaypresentwiththeclinicalpresentationof:

• RenalDisease–CKD,NephroticSyndrome

• Cardiacinvolvement–HeartFailure,arrhythmia,CAD

• GI/Liver–Hepatomegaly,Dysmotility

• Heme:BleedingRisk

• Musculoskeletal–Macroglossia,Muscleinfiltration,Arthritis

• Neuro:CarpalTunnelSyndrome,AutonomicNeuropathy,Stroke

• Other:Bruising,Periorbitalpurpura,Edema,JawClaudication,Hoarseness/voicechange

Amyloid - Workup •  FatpadaspirateandBoneMarrowmostrevealingofDxwithlowestrisk

•  Ifabovenegative,biopsyaffectedsite(or“random”biopsies)

• Oncefound,performamyloidtyping

• Workupforcause(althoughusuallyevident)

• Assesscardiac(Tp,BNP,CXR,Echo,EKG)andLiverfunction• AssesspresenceofacoagulopathywithPT/PTT/INR

Amyloid - Treatment • Guidedsymptomaticmanagement

•  ForAL–Similartomyeloma(Transplant/Chemo)

•  ForAA–Treat/Controlthedisease

A39-year-oldmanisevaluatedforalowerextremityrashandnumbnessofthearmsfor3weeks'duration.Hehasnorecenthistoryofacold,flu,orotherinfection.Hetakesnomedications.Onphysicalexamination,temperatureis99.2°F,bloodpressureis136/86mmHg,pulserateis66/min,andrespirationrateis12/min.BMIis24.Smallvascularinfarctionsareobservedontheearsandfingertips.Therearescatteredpalpablepurpuriclesionsonthebilaterallowerextremities,whicharelessprominentonthesoles.Strengthisreducedintherightwrist.Labsreveal:

ESR 66

C3 Normal

C4 Decreased

Cr 2.3

RF Positive

HCVAb Positive

Ua RBCCasts

Whatismostlikelytoestablishthediagnosis?1)  Anti-CCP2)  SPEP/UPEP3)  ANA4)  p-ANCA5)  SerumCryoLevels

Cryoglobulinemia

• Cryoglobulinsareproteinsthatprecipitatefromserumandplasmaattemperaturelessthanbodytemperature.Theydissolvewithwarming.

• Proteinsinvolvedareimmunoglobulinsalone,orinconjunctionwithcomplement.

•  Thepresenceoftheseproteinscanbeasymptomaticorcausevariableamountsofvasculitis,thrombosisorhyperviscosity

Cryoglobulinemia TypeI:PlasmaCellDiseasesandLymphoproliferativedisorder(BcellNHL,CLL)Monoclonalimmunoglobulin(IgG,IgM,orIgA)withnoRFactivityTypeII:HCV,SLE,Sjogren’s,lymphoproliferativedisordersPolyclonalimmunoglobulins+monoclonalimmunoglobulin(IgM,IgA)withRFactivityTypeIII:HCV,Chronicinflammatoryconditions(i.eendocarditis),RheumaticDisease(especiallySLE,Sjogren’s,vasculitis)&lymphoproliferativedisordersPolyclonalimmunoglobulinswithRFactivity

Cryoglobulinemia - Causes A32yearoldwithIVDruguseandcryoConsiderationsincludeHCVandEndocarditisA25yearoldmalewithhistoryofceliacdiseasethathascryo+palpablepurpura,arthritis,hematuriaandabdominalpainHSPA42yearoldfemalewithcryo,fevers,anacardiacexaminationwitha“flop”soundonauscultationAtrialMyxoma

Cryoglobulinemia Symptomsvaryonthetypebutbeonthelookoutfor:• Arthralgias• Neuropathy• Nephropathy• Digitalischemia• Acrocyanosis• Palpablepurpura•  Livedoreticularis•  Skinulcers/necrosis• Hyperviscosity• MPGNandsystemicvasculitis(CNS,Pulmonary,GI)

Cryoglobulinemia - Testing •  Testingneedstobedoneonwarmedsyringes•  SendRFandcomplementlevels• ConsiderESRandCRP• Workupforsuspectedunderlyingcondition

Cryoglobulinemia - Testing Workupforsuspectedunderlyingcondition• HepatitisC• PlasmaCellDisorders•  Leukemia(espCLL)• DruginducedVasculitis• AutoimmuneVasculitis(HSP,GPA,EPGA,mPA,SLE,RA,Sjogrens)•  InfectiousVasculitis(endocarditis,poststrep,Rickettsial,Malaria)• AntiphospholipidSyndrome•  TTP/HUS• AtrialMyxoma

Cryoglobulinemia - Treatment • Addresstheunderlyingcause

•  TypeI:Treatmalignancy+Hyperviscositytreatment(plasmapheresis)

•  TypeII/III:Treatdiseaseandvasculitissymptomswithrituximaborcyclophosphamide+glucocorticoids

Thank You